Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease such as arteriosclerosis. To date, there is still no effective antihypercholesterolemic agent commercially available that has found wide patient acceptance. The bile acid sequestrants seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
There are agents known, however, that are very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products compactin and mevinolin and a variety of semi-synthetic and totally synthetic analogs thereof. The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR1## wherein: R.sup.3 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sup.4 is: ##STR2## wherein B is R.sup.5 ##STR3## R.sup.5 is H or OH; and R.sup.6 is hydrogen or methyl; and a, b, c, and d represent optional double bonds, especially where b and d represent double bonds or a, b, c, and d are all single bonds; provided that where a is a double bond, B is ##STR4## PA1 R.sup.2 is CH.sub.2 OH or CO.sub.2 R.sup.3 ; and PA1 R.sup.3 is hydrogen, 2,3-dihydroxypropyl, C.sub.1-5 alkyl, C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; PA1 a, b, and c each represent single bonds or one of a, b, and c represents a double bond or both a and c represent double bonds; PA1 wherein Q is selected from a group consisting of: ##STR9## wherein z is 0 or 2 and P.sub.2 and P.sub.1 are independently lower alkyl or P.sub.2 and P.sub.1 together with the oxygens to which they are attached and the carbon bonded to the oxygens form a ring of 5 to 8 atoms; and PA1 wherein A is H or OH; and PA1 wherein R is: ##STR10## wherein: n is 0 to 5 PA1 R.sub.1 and R.sub.2 independently are hydrogen, C.sub.1-5 alkyl, or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached from a carbocyclic ring of 3 to 8 carbon atoms; PA1 R.sub.3 and R.sub.4 are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 alkylthio, phenyl, phenylthio or substituted phenyl in which the substituents are V and W and when n is 2 to 5, each of the R.sub.3 s and R.sub.4 s are independently hydrogen, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl or only one of the R.sub.3 s and R.sub.4 s is phenyl or substituted phenyl; PA1 R.sub.5 is hydrogen, halogen, hydroxy, C.sub.1-5 alkyl, phenyl or substituted phenyl in which the substituents are V and W, or R.sub.5 is a group selected from: PA1 V and W independently are hydrogen, halogen, hydroxy, trifluoromethyl, C.sub.1-3 alkyl, C.sub.1-3 alkyloxy or hydroxy-C.sub.1-3 alkyl; PA1 (i) a N,N'-carbonyl diazole, such as N,N'-carbonyldiimidazole or N,N'-carbonyldibenzimidazole or N,N'-carbonylbenzotriazole; ##STR14## wherein Z.sub.1 is C.sub.1-5 alkyl; and triethylamine; or (iii) a N-hydroxyamine such as N-hydroxysuccinimide or N-hydroxybenzotriazole in the presence of a diimide such as dicyclohexylcarbodiimide or N-ethyl-N'-(N,N-dimethylaminopropyl)-carbodiimide hydrochloride; PA1 (a) halogen, PA1 (b) hydroxy, PA1 (c) C.sub.1-10 alkoxy, PA1 (d) C.sub.1-5 alkoxycarbonyl, PA1 (e) C.sub.1-5 acyloxy, PA1 (f) C.sub.3-8 cycloalkyl, PA1 (g) phenyl, PA1 (h) substituted phenyl in which the substituents are X and Y, PA1 (i) C.sub.1-10 alkylS(O).sub.n in which n is 0 to 2, PA1 (j) C.sub.3-8 cycloalkylS(O).sub.n, PA1 (k) phenylS(O).sub.n, PA1 (l) substituted phenylS(O).sub.n in which the substituents are X and Y, and PA1 (m) oxo; PA1 (a) C.sub.1-10 alkyl PA1 (b) substituted C.sub.1-10 alkyl in which the substituent is selected from PA1 (c) C.sub.1-10 alkylS(O).sub.n, PA1 (d) C.sub.3-8 cycloalkylS(O).sub.n, PA1 (e) phenylS(O).sub.n, PA1 (f) substituted phenylS(O).sub.n in which the substituents are X and Y, PA1 (g) halogen, PA1 (h) hydroxy, PA1 (i) C.sub.1-10 alkoxy, PA1 (j) C.sub.1-5 alkoxycarbonyl, PA1 (k) C.sub.1-5 acyloxy, PA1 (l) phenyl, and PA1 (m) substituted phenyl in which the substituents are X and Y; PA1 (a) piperidinyl, PA1 (b) pyrrolidinyl, PA1 (c) piperazinyl, PA1 (d) morpholinyl, and PA1 (e) thiomorpholinyl; and PA1 (a) C.sub.1-10 alkyl, PA1 (b) phenyl, and PA1 (c) substituted phenyl in which the substituents are X and Y; PA1 (a) hydrogen; PA1 (b) C.sub.1-5 alkyl; PA1 (c) substituted C.sub.1-5 alkyl in which the substituent is selected from PA1 (d) 2,3-dihydroxypropyl; PA1 (1) hydrogen; PA1 (2) C.sub.1-10 alkyl; PA1 (3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from PA1 (4) C.sub.2-10 alkenyl; PA1 (5) C.sub.3-8 cycloalkyl; PA1 (6) aminocarbonyl; PA1 (7) substituted aminocarbonyl in which one or more substituent(s) is selected from PA1 (8) phenyl; PA1 (9) substituted phenyl in which the substituents are X and Y; PA1 (10) C.sub.1-10 alkylcarbonyl; PA1 (11) C.sub.3-8 cycloalkylcarbonyl; PA1 (12) phenylcarbonyl; PA1 (13) substituted phenylcarbonyl in which the substituents are X and Y; and PA1 (14) a nitrogen-containing heterocyclic group such as piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or the like formed by joining the substituents R.sup.6 and R.sup.7 to form a heterocyclic ring; and PA1 (a) R.sup.8 O(CH.sub.2).sub.m in which m is 0 to 3 and R.sup.8 is hydrogen, C.sub.1-3 alkyl or hydroxy-C.sub.2-3 alkyl; ##STR33## in which R.sup.9 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, naphthyl, amino-C.sub.1-3 alkyl, C.sub.1-3 alkylamino-C.sub.1-3 alkyl, di(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkylamino-C.sub.1-3 alkyl or di(hydroxy-C.sub.2-3 alkyl)amino-C.sub.1-3 alkyl; ##STR34## in which R.sup.10 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, phenyl or naphthyl; ##STR35## in which R.sup.11 and R.sup.12 independently are hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl or together with the nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or thiomorpholinyl; PA1 (e) R.sup.13 S(O).sub.n (CH.sub.2).sub.m in which R.sup.13 is hydrogen, C.sub.1-3 alkyl, amino, C.sub.1-3 alkylamino or di(C.sub.1-3 alkyl)amino; and PA1 (a) adding the substrate to a growing culture of Nocardia autotrophica for a suitable incubation period followed by isolation, and derivatization if desired; PA1 (b) collecting a culture of the bioconverting microorganism and contacting the collected cells with the substrate; or PA1 (c) preparing a cell-free, enzyme-containing extract from the cells of the bioconverting microorganism and contacting this extract with the substrate.
U.S. patent application Ser. No. 048,136, filed May 15, 1987, now abandoned, discloses biosynthetic and semisynthetic analogs of mevinolin and related compounds which possess a hydroxymethyl or a carbonyloxy group of structure --CO.sub.2 R.sup.3 substituted on the 6-position of the polyhydronaphthyl moiety and wherein R.sup.4 is ##STR5## wherein R.sup.1 is a broadly-defined acyl side chain which includes, among other groups, substituted and unsubstituted C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.1-10 alkenyl, C.sub.3-8 cycloalkyl and phenyl;
Said 6-hydroxymethyl and 6-carbonyloxy derivatives of mevinolin and analogs thereof are useful in treating hypercholesterolemia. However, comparative test data indicate that the 6-hydroxymethyl mevinolin analogs have a greater HMG-CoA reductase inhibiting effect than the 6-carboxy compounds. Thus there is a real need for the conversion of the 6-carboxy substituent into a 6-hydroxymethyl substituent in a minimum number of steps and without affecting the variety of other functionalities in the compound under conversion.